Ulcerative colitis (UC) and Crohn's Disease (CD) are inflammatory bowel diseases (IBD) characterized by chronic inflammation in the intestines. UC occurs in the colon while CD may be present in the entire gastrointestinal (GI) tract. The clinical symptoms are diarrhea, abdominal pain, occasional rectal bleeding, weight loss, tiredness and sometimes fever. Although occurring at any age, IBD is most common in teenagers and young adults, which consequently may suffer from delayed development and stunted growth. The frequency of the disease is similar to type 1 diabetes in Europe and the USA. The clinical course of IBD varies considerably. Patients with mild to moderate symptoms may be treated without hospitalization. However, 10-15% of patients experience a severe course of the disease, which in many cases is followed by surgery.
IBD is treated medically by reducing the inflammation and thereby controlling the gastrointestinal symptoms. However, there is currently no medical cure for IBD. Colonectomy may eliminate UC but reduces life quality and increases the risk of complications. The available medical treatments include the use of 5-aminosalicylic acid (5 ASA), corticosteroids and immunomodulatory medicaments. Prolonged treatment of mild to moderate IBD symptoms is usually carried out using 5 ASA while corticosteroids and immunomodulatory medicaments are used to treat severe symptoms. Diarrhea or abdominal pain appear as side effects of 5 ASA whereas long term use of corticosteroids frequently shows serious side effects including reduction in bone mass, infection, diabetes, muscle wasting and psychiatric disturbances. Immunomodulatory medicaments suppress the immune system, which controls the IBD symptoms. However, the resulting immuno-compromised state leaves the patient susceptible to many diseases.
IBD seems to be a result of an uncontrolled cascade in the immune response. The successful treatment of CD patients with antibodies against the pro-inflammatory cytokine TNF-α supports this assumption (Rutgeerts et al. 2004 Gastroenterology 126:1593-610). However, a prolonged antibody treatment will result in a general lowering of the TNF-α level, which eventually will lead to susceptibility to other diseases.
The reason for the chronic uncontrolled immune response in IBD has not been established. However, both genetic dispositions and the composition of the microbial flora residing in the intestinal tract of the patient are putative causes. Recently it has been reported that several hundred genes may be involved in a genetic disposition for IBD (Costello et al. 2005 PLoS Med 2(8): e199), which makes the development of a successful treatments through genetic strategies extremely difficult. Although it was found that Helicobacter pylori is the cause for peptic ulcer disease, no specific pathogens have been found to be the cause of IBD. However, it is generally believed that the commensal microorganisms in the GI tract are key factors in the exaggerated immune response in IBD patients (Schultz et al. 2003 Dig. Dis. 21: 105-128).
In vitro tests have shown that immune competent cells react differently upon contact to different bacteria (Christensen et al. 2002 J Immunol. 168:171-8). Bone marrow-derived dendritic cells (DC) are exposed to microbial strains and following the cytokines produced by the DC are determined. Predominant production of proinflammatory interleukins such as IL 6, IL12 and TNFα indicates a proinflammatory response upon exposure to a microbial strain. In contrast, a predominant secretion of anti-inflammatory interleukins such as IL4 and IL10 indicates an anti-inflammatory response upon the exposure. In general, microorganisms can be divided into two groups inducing pro-inflammatory or anti-inflammatory cytokines, respectively. In the following, such microorganisms are termed “pro-inflammatory” and “anti-inflammatory” microorganisms, respectively.
Irritable Bowel Syndrome (IBS) is part of a spectrum of diseases known as functional gastrointestinal disorders which include diseases such as non-cardiac chest pain, non-ulcer dyspepsia, and chronic constipation or diarrhea. These diseases are all characterized by chronic or recurrent gastrointestinal symptoms for which no structural or biochemical cause can be found. Patients suffering from IBD and IBS share several kinds of symptoms.
In 1907, the inventor of the modern immunology Elias Metchnikoff suggested that some intestinal bacteria have a beneficial role on the health. Today, these bacteria are termed probiotics defined as live microorganisms which administered in adequate amounts confer a beneficial health effect on the host.
A long range of effects have been postulated for instance that probiotics can help reduce the risk of certain diarrheal illnesses, improve the immune function, reduce the risk of cancer and cardiovascular diseases, assist lactose intolerant people etc. Some of the postulated effects have been investigated scientifically during the last two decades. In particular, research has been intense on the treatment of gastrointestinal diseases using probiotics. The rationale is that changing the microflora in the GI tract of IBD and IBS patients may reduce the immune aggressiveness thereby relieving the symptoms.
Today, three basic approaches exist for changing the microflora of the intestine, namely the use of i) antibiotics, ii) probiotics, and iii) synbiotics. The administration of antibiotics kills a subpopulation of the microflora while probiotics—if administered in appropriate amounts—are thought to displace some of the existing microorganisms in the intestine. Antibiotics and probiotics have also been used in combination. Synbiotics are mixtures of probiotics and substances—socalled prebiotics—that provide a substrate to specifically stimulate the growth of the probiotic microorganisms. None of these approaches—alone or in combination—have proven to be competent concerning a clear and a long term reduction of IBD or IBS symptoms.
Several strains of Lactic Acid Bacteria and species from the genus Bifidobacterium are probiotic, which implies that they one way or another have been shown to promote a specific health effect. Human clinical trials using probiotics alone or in combination with antibiotics have been performed to identify strains and/or formulations for the treatment of patients with IBD or IBS symptoms or for keeping already treated IBD patients in remission.
WO96/29083 and EP 554418 disclose three intestine colonizing lactobacillus strains including the two Lactobacillus plantarum strains 299 (DSM 6595) and 299v (DSM 9843) and Lactobacillus casei ssp. rhamnosus 271 (DSM 6594) which may be fermented in oat gruel. It is speculated that these strains may be used to treat IBS. EP 415941 discloses methods for preparing nutrient composition comprising treatment of oat gruel with enzymes before mixing with lactobacilli
The results from trials with Lactobacillus plantarum strains 299v administered in a daily total amount of up to 2×1010 colony forming units (cfu) in a fruit drink are ambiguous since some positive effects on IBS patients are reported in two studies (Nobaek et al. 2000 Am J Gastroenterol. 95:1231-8 and Niedzielin et al. 2001 Eur J Gastroenterol Hepatol. 13:1143-7) while a later study using the same strain showed no effect on the IBS patients (Sen et al. 2002 Dig Dis Sci 47:2615-20).
Other species of Lactobacillus have been tested as for instance Lactobacillus rhamnosus GG, which was administered in an amount of 6×109 bacteria twice a day for 52 weeks in a double blinded RCT study for preventing recurrence after curative resection for Crohn's disease (Prantera et al 2002 Gut 51:405-409). This study showed that the probiotic treatment had no effect compared to placebo.
Another strategy has been to use a combination of different probiotic strains, of which one product is called VSL#3. It consists of eight different bacterial strains and is administered as capsules possibly with freeze or spray dried bacteria. A recent study was performed with the administration to UC patients of 1.8×1012 VSL#3 bacteria twice a day for six weeks (Bibiloni et al. 2005 American Journal of Gastroenterology 100:1539-46). The patients had mild to moderate UC symptoms and the study was performed as an open study without placebo. Remission was achieved in 53% of patients.
In another study, 250 mg of the yeast Saccharomyces boulardii was administered three times a day for four weeks. Remission was obtained in 71% of the 17 UC patients (Guslandi et al. 2003 Eur J Gastroenterol Hepatol. 15:697-8). These results have not been confirmed in controlled studies.
A RCT study on maintaining remission of UC was performed recently using the E. coli Nissle strain (Kruis et al. 2004 Gut 53:1617-23).
Kato et al. (2004 Aliment Pharmacol Ther. 20:1133-41) and Ishikawa et al. (2003 J Am Coll Nutr. 22:56-63) have disclosed controlled trials assessing the effect of bifidobacteria-fermented milk on ulcerative colitis.
The number of microorganisms in the GI tract is approximately 1014 (Bäckhed et al. 2005 Science 307:1915-20). As mentioned previously, the results from clinical trials have shown that administration of large amount of probiotics may have a positive effect on the IBD symptoms. However, administration to IBD patients of more than 1012 VSL#3 microorganisms each day for several weeks led to the identification of only small amounts of only two of the provided eight strains in biopsies from the patients (Bibiloni et al. 2005 American Journal of Gastroenterology 100:1539-46). No dramatic change in the composition of the microflora was observed.
Hitherto, the general assumption in the scientific community concerning the treatment of IBD and IBS is that probiotics have shown some promising results but are not sufficient effective (Schultz et al. 2003 Dig. Dis. 21:105-28 and Kim et al. 2003 Aliment Pharmacol Ther. 17:895-904).
In summary, the current applied strategies for treating IBD or IBS using probiotics aiming to change the composition of the GI microflora cover—alone or in combination—i) oral administration of different amounts of probiotic microorganisms also including concomitant administration of conventional medicines like 5 ASA, ii) oral administration of substrates specifically favourable to the growth of probiotic microorganisms, iii) short term oral administration of antibiotics and iv) the use of probiotic microorganisms capable of transiently colonizing the intestine and/or producing compounds that are toxic to other bacterial species. These strategies have not proven to be sufficiently effective neither in reducing the symptoms experienced by IBD and IBS patients nor changing the composition of the microflora in the intestines.
Recently, it has been reported that a randomized controlled trial (RCT) comprising a three months treatment of UC patients with retarded release of phosphatidylcholine (PC) in the colon has shown a remission in 53% of the patients (Stremmel et al. 2005 Gut 54:966-971).